Biology subjects

Zhu, W.-G.

Publications and source records attributed to Zhu, W.-G..

3 recordsLinked to original sources

bioRxiv2024

GATAD2B containing NuRD complex drives R-loop dependent chromatin boundary formation at double strand breaks

Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, the regulation of the open and condensed chromatin architecture is still unclear. In this study, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and R-loop-dependent manner, to promote histone deacetylation and chromatin condensation, creating a temporal boundary between open and closed chromatin. This boundary is necessary for correct DNA end resection termination. The lack of the GATAD2B-NuRD complex leads to chromatin hyper-relaxation and extended DNA end resection, resulting in HR repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and chromatin landscape and underscore its biological significance in the RNA-dependent DNA damage response.

molecular biology↗

bioRxiv2022

A novel Vps34 complex constrains loop extrusion-mediated P-H2A spreading

The establishment of appropriate phosphorylated histone H2AX ({gamma}H2AX) foci is required for the precise initiation of DNA damage response (DDR) signaling, which contributes to the efficient repair of DNA double-strand breaks (DSB)1. Therefore, it is important to understand exactly how {gamma}H2AX foci are established in response to DSB. Recently, an attractive mechanism has been proposed to explain this process2. DSB-anchored cohesin-mediated loop extrusion promotes H2AX-containing chromatin to pass through DSB-recruited ATM, by which H2AX is phosphorylated to form {gamma}H2AX foci on each side of the DSB. The loop extrusion-promoted enlargement of {gamma}H2AX-modified chromatin is halted upon cohesin encountering boundary factors such as CTCF. This cohesin-dependent mechanism was shown to be conserved among eukaryotic cells, because deletion of the cohesin regulator Pds5 in budding yeast also results in extended spreading of phosphorylated H2A at Ser129 (P-H2A)2. However, yeast lacks CTCF or CTCF-like boundary factors that restrict cohesion-mediated loop extrusion. Here, we report a novel vacuolar sorting protein 34 (Vps34) complex, which might function as a boundary factor that constrains cohesin-dependent loop extrusion-mediated P-H2A spreading.

molecular biology↗

bioRxiv2020

A synergistic action of sirtuins directly recognizes DNA breaks and potentiates DNA damage response and repair

The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to {gamma}H2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair.

biochemistry↗